Polyoxyethylene derivatives as antipruritic ectoparasiticide

ABSTRACT

Certain ethoxylates have been found to exhibit concurrent activities of particular merit in the treatment of ectoparasitic infestations.

This is a division of application Ser. No. 429,444, filed Sept. 30, 1982(now U.S. Pat. No. 4,497,831) which is a division of application Ser.No. 4,299, filed Jan. 17, 1979 (now U.S. Pat. No. 4,372,977) which, inturn, is a continuation of application Ser. No. 802,012, filed May 31,1977, now abandoned.

BACKGROUND OF THE INVENTION

Ectoparasites such as lice and mites cause pruritus or pain in theiranimal or human hosts. Therapy which simply kills the parasite leavesthe host with subcutaneous or intradermal residues which continue toitch for significant time periods after the infestation is extinguished.Furthermore, scratching during and after the episode frequently leads topainful excoriation.

It has now been found that certain ethoxylates exhibit insecticidaland/or ovicidal activity. The same boundaries which delimit theinsecticidal properties also include compositions which have a valuabledegree of topical anesthetic performance. Although chemically unrelatedto any of the conventional anesthetic configurations, these ethoxylatesdemonstrate topical pharmacologic properties which can be variouslycharacterized as analgesic, anesthetic or antiprurtic.

V. B. Wigglesworth (Journal of Experimental Biology, 21, 3, 4 p. 97(1945)) in a study of transpiration through insect cuticles, reported onthe moisture loss of Rhodnius nymphs following treatment with varioussurfactants. He observed that the ethoxylates of ring compounds had verylittle action, and that the eight mole ethoxylate of cetyl alcohol wasthe most effective surfactant be tested, the nymphs losing 48% of bodyweight in 24 hours. Wigglesworth failed to appreciate that this effectcould be adapted to killing insects by an action having no counterpartin higher animals.

Maxwell and Piper (Journal of Economic Entomology, 61, No. 6, December1968 p. 1633) explored the lethal activity of a large series ofethoxylates against southern house mosquito pupae. They found activityat high dilutions (in the parts per million range), but contrary toWigglesworth, they reported greatest activity with some ethoxylates ofalkylphenols.

In tests against lice and their ova, we have made certain discoverieswhich were unexpected in light of Maxwell and Piper, and Wigglesworth.We found efficacy only at concentrations several orders of magnitudegreater than Maxwell and Piper. Where they reported that short ethyleneoxide chain lengths were less effective than 4-6 moles of ethyleneoxide, we discovered that the aryl alkyl ethoxylates were best at 1-3moles of ethylene oxide, and that such compounds were good ovicides butmediocre pediculicides. Certain ethoxylates of aliphatic alcohols weremuch superior both as insecticides and as ovicides. Moreover, those mosteffective as toxicants were also found to be most effective as topicalanesthetics.

The ethoxylates of this invention are well known as surface activeagents and have been incorporated in many pharmaceutical and cosmeticpreparations as such. For example, polyoxyethylene (4) lauryl ether is5.5% of a washable coal tar ointment, polyoxyethylene (23) lauryl etheris 8% of an all purpose anionic emulsion for skin application, and amixture of these two lauryl ethers constitutes 35% of a commercial tarshampoo.

Smith (U.S. Pat. No. 2,666,728) teaches the use up to 5% of a nonionicpolyethylene oxide ether of aromatic glycols in a composition fordestroying lice. Lindner (U.S. Pat. No. 2,898,267) teaches the use ofethoxylates in emulsifiers for acaricidal compositions.

It is the object of this invention to provide new, safe and effectivetoxicants for lice and their ova. This and other objects of theinvention will become apparent to those skilled in the art from thefollowing detailed description.

SUMMARY OF THE INVENTION

This invention relates to ectoparasiticidal toxicants and a method ofcontrolling ectoparasites and the pain or itch related to infestation.More particularly, the invention relates to the use of certainethoxylates as toxicants for lice and/or their ova, and for mites, totoxicant compositions containing such ethoxylates and to suchethoxylates as adjunctive therapy to relieve pain or itch.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The toxicants of the instant inventin are certain ethoxylates i.e.,certain derivatives of polyoxyethylene [H(OCH₂ CH₂)_(n) OH]. Thepolyoxyethylene glycols per se have not been found to be pediculicidalor ovicidal. For convenience, the polyoxyethylene will hereinafter bereferred to as POE and the number of repeating units (n) will beindicated in parenthesis where applicable.

The POE derivatives which exhibit toxicant properties are the alkylethers, alkyl esters and block polymers of polyoxypropylene and/orethylenediamine. Thus, the alkyl or ester moiety, derived from a fattyalcohol or fatty acid respectively, contains 12 to 24 carbon atoms andpreferably 12 to 20 carbon atoms. The alkyl moiety is preferablyunsubstituted but can, if desired, contain an aryl substituent. Theblock polymers contain 6 to 100 POE units and 30 to 112 units ofpolyoxypropylene.

It has been observed that the POE alkyl ethers, alkyl esters and blockpolymers of polyoxypropylene and/or ethylendiamine require anappropriate hydrophilic-lipophilic balance (HLB) for good activity. Ingeneral, the HLB can be about 2.5 to 13.5. The alkyl ethers appear toexhibit maximum activity at an HLB in the neighborhood of 9, and thealkyl esters and block polymers at a lower HLB, excepting the alkyldiester, POE (8) dilaurate, having an HLB value of 10.

Exemplary of the POE alkyl ethers of the present invention are POE (1)lauryl ether, POE (2) oleyl ether, POE (2) stearyl ether, POE (3) oleylether, POE (3) tridecyl ether, POE (4) myristyl ether, POE (5) oleylether, POE (6) tridecyl ether, POE (10) oleyl ether, and the like. POE(1) ethylphenyl ether and POE (3) octylphenyl ether are examples ofsomewhat effective POE aryl alkyl ethers.

Typical examples of the POE esters include POE (3) oleate, POE (2)laurate, POE (8) dilaurate, and the like. Typical examples of the blockpolymers include Poloxamer 401, Poloxamer 181 and the like.

One or more of the toxic ethoxylates of the present invention can beincorporated into an active toxicant composition which can be in theform of a liquid, powder, lotion, cream, gel or aerosol spray, or foamas the result of formulation with inert pharmaceutically acceptablecarriers by procedures well known in the art. Any pharmaceuticallyacceptable carrier, whether aqueous or not aqueous, which is inert tothe active ingredient can be employed. By inert is meant that thecarrier does not have a substantial detrimental effect on thepediculicidal or ovicidal toxicant activity of the active ingredient.

The carrier may also be additive or synergistic to the primary activeingredient.

The active ethoxylate is incorporated into the toxicant composition usedto treat the substrate in need of such treatment, believed to be in needof such treatment, or desired to be prophylactically protected in aneffective toxicant amount. By such amount is meant the amount which willcause at least 50% of the ectoparasites exposed in the two minuteimmersion tests described below to die within 24 hours in the case oflice and within 2 weeks in the case of ova. The minimum concentration ofethoxylate in the composition required to provide an effective toxicamount varies considerably depending on the particular ethoxylate, theparticular inert pharmaceutically acceptable carrier being employed andany other ingredients which are present. Thus, in one case a 10%concentration may suffice, while in other cases, concentrations as highas 30 to 40% may be required to obtain an effective toxic dose.

The two minute immersion test referred to above is carried out asfollows:

Pediculicidal activity: A 50 ml beaker is filled with tap water andallowed to come to room temperture (about 24° C.). Ten young adult maleand ten young adult female lice (Pediculus humanus corporis) of the sameage group and from the same stock colony are placed on a 2×2 cm coarsemesh patch. The sample to be tested, maintained at room temperature, isshaken until homogeneous and placed into a 50 ml beaker. The mesh patchis placed into the sample immediately after pouring, allowed tosubmerge, and after two minutes is removed and immediately plunged intothe beaker containing the tap water. The patch is vigorously agitatedevery ten seconds and after one minute the patch is removed and placedon paper toweling. The lice are then transferred to a 4×4 cm blackcorduroy cloth patch and this point of time is considered zero hours.Thereafer, the corduroy patch is placed in a petri dish which is coveredand stored in a 30° C. holding chamber.

Ovicidal activity: 15 adult, 5 to 10 day old, female lice (Pediculushumanus corporis) are placed on a 2×2 cm nylon mesh patch which isplaced in a petri dish, covered and maintained in an incubator at 30° C.for 24 hours. The adult lice are then removed and the number of plump,viable eggs and shriveled nonfertile eggs on the patch are recorded. Thesample to be tested, maintained at room temperature, is shaken untilhomogeneous and poured into a 50 ml beaker. Immediately after thepouring, the mesh patch is placed into the beaker, allowed to submerge,and after two minutes is removed and immediately plunged into a 50 mlbeaker containing tap water at room temperature (about 24° C.). Thepatch is vigorously agitated every ten seconds and after one minute, thepatch is removed and placed on paper toweling for one minute. The patchis then placed in a petri dish which is covered and stored in the 30° C.incubator. Fourteen days following treatment, the number of hatched eggsand the number of shriveled or unhatched eggs is noted.

In both the pediculicidal and ovicidal two minute immersion test,controls are run in identical manners to that described, with roomtemperature (24° C.) tap water substituted for the sample to be tested.The results of the tests reported are net results.

In the following tables, the results of pediculicidal and ovicidaltesting for various toxicants of this invention are set forth. Thematerials were tested in undiluted form (neat) or in a combination (C)containing 15% (w/w) compound, 25% isopropanol and 60% water. Forcomparative purposes, results achieved with the unmodified ethoxylate,i.e., polyethylene glycol (PEG) and other ethoxylates not within thescope of this invention are also set forth.

                  TABLE 1    ______________________________________    Pediculicidal and ovicidal activity for    ethoxylate alcohols having a general structure type    H(OCH.sub.2 CH.sub.2).sub.n OH.                    % Mortality                    Pediculicidal                              Ovicidal    Compound     n        Neat   C      Neat C    ______________________________________    diethylene glycol                  2        0      5      0   54    PEG 12       12       25     35     35   16    PEG 32       32       (1)    20     0(2)  0    PEG 75       75       (1)    15     0(2) 14    ______________________________________

                  TABLE II    ______________________________________    Pediculicidal and ovicidal activity for a    series of alkyl ethoxylate ethers                      % Mortality                      Pedi-                      culicidal                              Ovicidal    Compound         HLB    Neat    C   Neat  C    ______________________________________    POE  (1)    lauryl ether 3.6  100   40  100(3)                                                  100    POE  (2)    oleyl ether  4.9  100   10  100(3)                                                  100    POE  (2)    stearyl ether                             4.9  100   40  100    33    POE  (3)    oleyl ether  6.6  100   10  100    41    POE  (3)    tridecyl ether                             8    100   20  100   100    POE  (4)    myristyl ether                             8.8  100   35  100(3)                                                  100    POE  (5)    oleyl ether  8.8  100   15  100   8.3    POE  (4)    lauryl ether 9.5  100   30  100    83    POE  (6)    tridecyl ether                             11   100   30  100    0    POE  (6.5)  tridecyl ether                             11.6 100   15  100    34    POE  (6)    lauryl thioether                             11.6 100   20  100    0    POE  (10)   oleyl ether  12.4 100   10   5     68    POE  (7)    lauryl ether 12.5 100(4)                                         0  100(4)                                                   36    POE  (8)    lauryl thioether                             13.4  75   20   67    0    POE  (9)    lauryl ether 13.6 100   20  100(3)                                                   19    POE  (10)   lauryl thioether                             13.9  15    5   30    0    POE  (12)   lauryl ether 14.5  20    5  100    0    POE  (20)   isohexadecyl ether                             15.7 (1)    0  11(2)  2    POE  (23)   lauryl ether 16.9 (1)    0  69(2)  3    ______________________________________

                  TABLE III    ______________________________________    Pediculicidal and ovicidal activity for some    arylalkyl ethoxylate ethers.                      % Mortality                      Pediculicidal                               Ovicidal    Compound         HLB    Neat    C    Neat  C    ______________________________________    POE  (1)    octylphenyl ether                             3.6  80    10   100(3)                                                   66    POE  (3)    octylphenyl ether                             7.8  15    5     82(3)                                                   34    POE  (10)   nonylphenyl ether                             13.4 20    5     82(3)                                                    0    ______________________________________

                  TABLE IV    ______________________________________    Pediculicidal and ovicidal activity for    ethoxylate mono and diesters                    % Mortality                    Pediculicidal                             Ovicidal    Compound      HLB     Neat   C     Neat  C    ______________________________________    POE  (2)    oleate    3.5   70   75    100(3)                                                 14    POE  (2)    laurate   6.0   25   20    100(3)                                                 6.5    POE  (8)    dioleate  7.2   40    0    7.3   28    POE  (2)    laurate   7.4   95   55    100(3)                                                 8.3    POE  (8)    distearate                          7.8   (1)  40    (1)   23    POE  (4)    laurate   8.6   10   15     14   5.9    POE  (4)    sorbitol  9      5   20     77   21                septaoleate    POE  (8)    dilaurate 10    80   10     23   38    POE  (12)   distearate                          10.6  (1)  40    (1)   24    POE  (20)   stearate  15    (1)   0    (1)   0    POE  (100)  stearate  18.8  (1)   0    (1)   5    ______________________________________

                  TABLE V    ______________________________________    Pediculicidal and ovicidal activity for    ethoxylate block polymers having the general structure type    outlined for each section.                   % Mortality                   Pediculicidal                              Ovicidal    x    y       z      HLB    Neat C      Neat   C    ______________________________________    (A) based on structure type     ##STR1##    18   14      18     4.5    10   0       56    4.8    12   23      12     8.4     5   0       0     15     7   22       7     10.8   10   0       0     41    (B) based on structure type     ##STR2##     3   30       3     3      10   0       70    0    13   67      13     4      --   10      0(2)  1.2     6   67       6     5      55   0       80    84     8   30       8     7       0   50      8.4   0    21   67      21     8      (1)  10      0(2)  4.5    13   30      13     15      5   20      0     17    38   54      38     15     (1)  0       0(2)  19    122  47      122    27.5   (1)  40       (1)  4.5    (C) based on structure type     ##STR3##    18    2             2       5   20      79    0    12    2             3      45   0       73(3) 11    21    7             3.5    30   0      100(3) 53    26    8             5       5   0      100(3) 49    13    4             7       0   20      58    0    26   24             13     85   0       --    20     8    7             16      0   20      0     28    ______________________________________

Notes to Tables I-V

(1) Solid--could not be tested at 100%

(2) 50% (w/w) in ethanol

(3) pad noted to be coated with compound at conclusion of test

(4) 90% (w/w) in water

The pediculicidal activity of various compounds set forth in Table II asa function of concentration was determined in a diluted systemcontaining 25% isopropanol and water q.s. The results are shown in TableVI.

                  TABLE VI    ______________________________________    Concentration, % (w/w)    Mortality, %    ______________________________________    A.  POE (1)    lauryl ether                               HLB = 3.6                   10                   55                   15                   40                   20                   80                   30                   85                   40                   80                   50                   95    B.  POE (2)    oleyl ether HLB = 4.9                   10                   30                   15                   10                   20                   35                   30                   15                   40                   20                   50                   35    C.  POE (2)    stearyl ether                               HLB = 4.9                   10                    0                   15                   40                   20                   80                   30                   50                   40                   100                   50                   100    D.  POE (3)    oleyl ether HLB = 6.6                   15                   10                   20                   15                   30                   60                   40                   70                   50                   100                   60                   100    E.  POE (3)    tridecyl ether                               HLB = 8                   10                   25                   15                   20                   20                   95                   30                   95                   40                   100                   50                   100    F.  POE (4)    myristyl ether                               HLB = 8                   10                   75                   15                   35                   20                   90                   30                   100                   40                   100                   50                   100    G.  POE (4)    lauryl ether                               HLB = 9.5                   10                   15                   15                   30                   20                   55                   30                   80                   40                   85                   50                   60    H.  POE (6)    tridecyl ether                               HLB = 11                   10                   40                   15                   30                   20                   65                   30                   75                   40                   35                   50                   55    I   POE (6.5)  tridecyl ether                               HLB = 11.6                   15                   15                   20                   25                   30                    5                   40                   35                   50                   30                   60                   60    J.  POE (7)    lauryl ether                               HLB = 12.5                   15                    0                   20                   10                   30                   20                   40                   20                   50                   35                   60                   40    K.  POE (9)    lauryl ether                               HLB = 13.6                   15                   20                   20                   25                   30                   15                   40                   25                   50                   70                   60                   50 15 -L. POE (12) lauryl ether HLB =                                        14.5                   15           5                   40                    0                   50                   15                   60                   30                   70                   45    M.  POE (23)   lauryl ether                               HLB = 16.9                   15                    0                   20                    0                   30                    0                   40                    0                   50                    0                   60                    5    ______________________________________

The pediculicidal activity of two ethoxylated alkyl ethers as a functionof concentration when diluted with water was determined and the resultsare set forth in Table VII.

                  TABLE VII    ______________________________________    Concentration, % (w/w)  Mortality, %    ______________________________________    A.    POE (2)  oleyl ether                              HLB = 4.9                    5                  0                    10                 10                    20                 35                    30                 90                    40                100                    60                100                    80                100                   100                100    B.    POE (4)  lauryl ether                              HLB = 9.5                    5                  5                    10                 5                    15                 45                    20                100                    80                100                    90                100                   100                100    ______________________________________

The ovicidal activity of various compounds set forth in Table II as afunction of concentration was determined in a diluted system containing25% isopropanol and water q.s. The results are shown in Table VIII.

                  TABLE VIII    ______________________________________    Concentration, % (w/w)   % Mortality    ______________________________________    A.  POE (1)   lauryl ether                              HLB = 3.6                   1                   100                   3                   100                   5                   100                   7                   100                   9                   100    B.  POE (3)   tridecyl ether                              HLB = 8                  10                   100                  15                   100                  20                   100                  30                   100                  40                   100    C.  POE (4)   myristyl ether                              HLB = 8.8                  10                    27                  15                   100                  20                   100                  30                    92                  40                   100                  50                   100    D.  POE (6)   tridecyl ether                              HLB = 11                  10                    0                  15                    0                  20                    16                  30                    44                  40                    14                  50                    3    E.  POE (12)  lauryl ether                              HLB = 14.5                  15                    0                  30                    0                  40                   0.2                  50                    5                  60                    2                  70                    0    F.  POE (23)  lauryl ether                              HLB = 16.9                  15                    3                  20                    10                  30                    4                  40                    5                  50                    0                  60                    5    ______________________________________

Table IX reflects the resulting pediculicidal and ovicidal activity of a15% (w/w) concentration of POE (4) lauryl ether with variation ofisopropanol and water content

                  TABLE IX    ______________________________________                      % Mortality    % w/w isopropanol                % w/w water Pediculicidal                                        Ovicidal    ______________________________________    25          60          30          83    20          65          30          21    15          70          15          19    10          75          15          15     5          80          95          100     1          84          20          100     0          85          45          10    ______________________________________

As can be seen from Table IX, the 15% concentration of POE (4) laurylether exhibited synergistic pediculicidal activity when the isopropanolwas about 1-5%.

The most effective toxicants of this invention have also been found toexhibit topical anesthetic activity. Thus, for example, one drop of 5%aqueous POE (4) lauryl ether caused an onset of corneal anestheticaction in about 5-8 minutes with a duration of about 0.5-4 hours(average four tests was two hours) in a modified Cole and Rose rabbiteye iritiation test (J. Lab. & Clin. Med. 15:239, 1929). In contrast,POE (23) lauryl ether did not exhibit any activity in the same test. Ingeneral, the preferred alkyl ethers exhibit anesthetic, analgesic orantipruritic activity at concentrations of at least 1% and arepreferably employed for this purpose at about 1-10%.

The miticidal activity of some of the instant toxicants was determinedas follows. Into a one cubic foot chamber, held at room temperature, isplaced a covered microscope depression slide containing ten adult mixedsex mites, Psoroptes equi var. cuniculi. The slide is positioned at adistance of ten inches horizontally and four inches below the activatorof a mechanical spray device and uncovered. The mechanical pump spraydevice delivers 50 micrograms of sample per depression of the activator.The sample to be tested, maintained at room temperature, is shaken untilhomogeneous and placed in the mechanical pump spray device. The primedactivator is depressed twice, releasing 100 micrograms of spray mistinto the closed chamber. The mist is allowed to settle and the slidecontaining the mites is removed and covered. This point of time isconsidered zero hours. The covered slide is then held at roomtemperature for 24 hours. Microscopic observations are noted at 0, 1, 3,and 24 hours post treatment. Controls are run in an identical manner asthat described using water or the diluting agent, and net mortalityresults are reported.

Table X shows the miticidal activity of a 50% (w/w) concentration of thenamed compounds in isopropanol.

                  TABLE X    ______________________________________    Compound         HLB    Miticidal Activity, %    ______________________________________    POE (1)  lauryl ether                         3.6    100    POE (2)  oleyl ether 4.9     80    POE (4)  myristyl ether                         8.8    100    POE (4)  lauryl ether                         9.5    100    POE (6)  tridecyl ether                         11      90    POE (10) oleyl ether 12.4   100    POE (12) lauryl ether                         14.5   100    ______________________________________

As noted, various end use formulations can be prepared. Some typicalformulations are set forth and the amounts recited are percentages byweight:

Liquid pediculicide and ovicide suitable for mechanical sprayapplication or inunction.

    ______________________________________    POE (8) dilaurate            15    Isopropanol                  60    Water                        25    Liquid pediculicide and ovicide shampoo    POE (4) lauryl ether         26.0    POE (23) lauryl ether        7.7    Isopropanol                  7.7    Benzalkonium chloride        0.2    Water                        58.4    Ovicidal powder    POE (3) tridecyl ether       3    Pyrophyllite                 97    Pediculicidal and ovicidal powder    POE (1) lauryl ether         10    Prophyllite                  90    Pediculicidal Stick    POE (2) oleyl ether          15.0    Sodium stearate              8.0    Sorbitol                     3.5    Isopropanol                  25.0    Ethanol                      39.0    Water                        9.5    Pediculicidal and ovicidal quick breaking aerosol foam    POE (4) lauryl ether         20    Water                        72    Isobutane                    8    Pediculicidal and ovicidal gel    POE (2) oleyl ether          15.0    Isopropanol                  25.0    Carbomer 940                 0.5    Triethanolamine              0.38    Water                        59.12    ______________________________________

As noted, various changes and modifications can be made in the instantinvention without departing from the spirit and scope thereof. Thevarious embodiments disclosed herein were made for the purpose offurther illustrating the invention but were not intended to limit it.Throughout this specification and claims, all temperatures are indegrees Centigrade and all parts and percentages are by weight unlessotherwise indicated.

We claim:
 1. A method of controlling ectoparasites or their ova whichcomprises applying to a human or animal host in need of such control, aneffective toxic amount of at least one derivative of polyoxyethylenehaving an HLB of about 2.5-13.5, said derivative being an alkyl estercontaining 12 to 24 carbon atoms thereof.
 2. The method of claim 1wherein said ester moiety contains 12 to 20 carbon atoms.
 3. The methodof claim 1 wherein said derivative is employed in combination with aninert pharmaceutically acceptable carrier.
 4. The method of claim 3wherein said carrier is an aqueous carrier.
 5. The method of claim 1wherein said derivative is polyoxyethylene (2) oleate, polyoxyethylene(2) laurate of HLB 7.4 or polyoxyethylene (8) dilaurate.
 6. The methodof claim 1 wherein said ectoparasite is lice.